Muscle in health and disease

The overall aim is to advance the understanding of the pathogenesis of inherited cardiac and skeletal muscle disorders, to define the genetic cause, mechanisms of disease development, and thereby give the basis for advances to identify new therapeutic targets.

The sarcomere is the functional unit of both cardiac and skeletal muscle contraction. Mutations in sarcomeric proteins are known to cause increasing number of different cardiac and skeletal muscle diseases.

Dysfunctional mutations in sarcomeric proteins are the important causes of the hypertrophic cardiomyopathies (HCM) and skeletal myopathies. The range of clinical and morphological manifestations in patients with sarcomeric myopathies is wide. Variability in clinical manifestations in patients with HCM ranges from benign course with minimal symptoms to progressive disease and development of heart failure and sudden death. The skeletal myopathies vary in severity from paralysis at birth to mild conditions compatible with normal life span.

We identify and characterize new inherited muscle diseases. Although many disease genes have been identified and our studies have led to identification of new muscle diseases, the insights in their pathogenesis and the pathophysiology of the diseases remains obscure. Therefore, the development of genetically engineered models to be able to verify mutations as being pathogenic and to study functional and structural consequences of such mutations is the valuable goal.

We develop disease models for cardioskeletal muscle diseases in Drosophila and use human skeletal muscle cultured cells to verify mutations as being pathogenic and to study functional and structural consequences ofsuch mutations. The research project also integrates molecular, physiological and protein-structure technologies to investigate functional properties of the proteins and to clarify important questions on the molecular mechanisms leading to the phenotypes of the muscle diseases. Harnessing and integrating genetically engineered models and molecular and physiological technologies are powerful tools to determine how different mutations affect the structure, stability, and function of protein constituents of sarcomeric muscle filaments. Results from these studies would further our understanding of the mechanism of pathogenesis for each of these diseases. Emerging insights from models of diseases should provide powerful leads for the identification of potential therapies to prevent disease progress.